Method of preparing 1, 4-pregnadienes



United States Patent Ofilice 3,021,346 Patented Feb. 13, 1962 METHOD OF PREPARING 1,4-PREGNADIENES Sidney Fox, Spring Valley, and Mitchell Stanley Blicharz,

Blauvelt, N.Y., and Victor Emil Origoni, Emerson,

N.J., assignors to American Cyanamid Company, New

York, N.Y., a corporation of Maine No Drawing. Filed Jan. 21, 1958, Ser. No. 710,189

7 Claims. (Cl. 260397.45)

This invention relates to an improved method of preparing 1,4-pregnadienes. More particularly, it relates to an improved yield by the selective release of the product from a selenium intermediate.

The preparation of A steroids from the corresponding A steroid has been described in the chemical literature. For example, Ringold et al., J. Org. Chem. 21, 239-40 (1956), describes the use of selenium dioxide in the preparation of A androstadiene-l7B-o1-3-one from testosterone.

Florey and Restivo, J. Org. Chem. 22, 406-409 (1957), describe the selenium derivatives of A -3-keto steroids that are formed by the action of A -3-keto steroids with selenium dioxide. They repeated the work of Ringold, et al., and obtained yields of 12% of A steroid and 6% of a seleno A compound using a chromatographic separation of the products. The mother liquor of the above reaction was also processed chromatographically and yielded no additional A steroid.

In the above mentioned reference Florey and Restivo describe an experiment that shows that the selenium derivative does not form from the A product. The implication is that the selenium derivative is an intermediate in the A formation. This is also substantiated in a publication by a Japanese worker, Miki, J. Pharm. Soc. Japan, 75, 403 (1955). Miki isolated a monoselenium compound (in the related field of santonin chemistry) and on pyrolysis obtained a 30 to 40% yield of dienone.

. We have now found that senenium dioxide oxidation of A -3-keto steroids may be carried out under ideal conditions in yields of 50 to 70% of the desired A -3-keto compound. This is accomplished by reacting the combined reaction product with a specially treated Raney nickel catalyst. Not only does this procedure efiect increased yields, but it can also be shown that the products contain less residual selenium than do the non-nickel treated products.

The steroids on which the process of the present invention have been found particularly useful result in the compounds having the general formula:

---orr T T in which R is a member of the group consisting of hydro- .tate that forms.

in the process of the present invention the 4-pregnene is reacted with selenium dioxide followed by the conversion of the selenium intermediate to the desired 1,4-pregnadiene. The usual method is the use of chromatographic separation to isolate the A compound which still has a comparatively high selenium content as shown hereinafter in Example 1.

We have found that the use of acetic acid treated Raney nickel catalyst produces a product in high yield containing a low selenium content.

A further advantage of our process is that it will more readily lend itself to commercial production since a chromatographic isolation is not required. The reaction with the partially deactivated Raney nickel preferably carried out at room temperature, although it will take place at a temperature of from 0 to 50 C. i The reaction is completed in a period of from 30 minutes to several hours.

The Raney nickel is acid treated before use because it afiords a better control over the process than does nonacid treated nickel. When fully active (non-treated) Raney nickel is used, there is a possibility of the reduction of the A and A bonds. Ideal results have been obtained with the partially deactivated Raney nickel prepared by mixing one part of Raney nickel with live Volumes of dilute acetic acid (5 to 40% and allowing the mixture to stand ten minutes to several hours. The acetic acid is then removed, the Raney nickel Washed twice with water and finally twice with alcohol. In using the partially deactivated Raney nickel, one to five parts are used for each part of steroid.

The following examples show in detail the use of partially deactivated Raney nickel for the preparation of A -3-keto steroids of the present invention.

Example 1 chloride. The methylene chloride solution is Washed with (a) 10 ml. of water, (b) 10 ml. dilute potassium bicarbonate, and (c) 10 ml. water, successively. The washed methylene chloride is allowed to stand for four hours and is then filtered to remove any red selenium precipi- The filtrate is treated with activated carbon. Five ml. of water and 3 grams of resin IR 4B are added to the dried methylene chloride extract and agitated for 10 minutes. After filtering the phases are sepa rated and the methylene chloride dried over magnesium sulfate. On evaporation to dryness, the residue weighs 1.2 grams. The 1.2 grams residue is dissolved in 5 ml. of the mobile phase and 5 ml. stationary phasejmixed with 10 grams of diatomaceous earth and applied to a column (see below for column preparation), subsequently eluting with the mobile phase. In all, twenty-twofractions of 40 ml. are collected. Paper chromatographic analysis indicated the presence of l6a,2l-diacetoxy 11 3,-

l7u-dihydroxy 9a-fiuoro-l,4-pregnadiene 3,20-dione in fractions 9-22. Fractions- 922 are evaporated to dryness. The residue is dissolved in ethyl acetate, treated with activated carbon at 40 C., filtered and the filtrate is taken to dryness. The residue is dissolved in 5 ml. of toluene and, upon adding 1 to 2 drops of ethyl acetate,

residueisdissolved in 250ml. of methanol.

crystals are formed. After allowing to stand, the crys talsare washed with cold toluene. The crystals are-recrystallized out of ethyl acetate with petroleum ether. Two crops are obtained, yielding the following results:

Ohromatogram Optical rotation (0.507 in CHOli). Melting point (C.) Selenium content (p.p.m.)

Homogeneous A Homogeneous A +19.7 +18.7.

Column preparation.Mix 667 ml. of chloroform, 400 ml. of petroleum ether (90-100" C.) and 133 ml. ethylene glycol. Upon equilibration, two phases are formed; the upper mobile phase, and the lower stationary phase. Mix

(c) slurried with 5 ml. of partially deactivated Raney nickel for one hour, filtered and repeated the treatment.

(0!) Slurried for one hour with 5 ml. of active Raney nickel catalyst, filtered off the catalyst and treated the filtrate one hour with partially deactivated Raney nickel.

(e) Slurred fortwo hours with .25 ml. of partially deactivated Raney nickel.

The spent catalyst is removed by filtration and the filtrates are evaporated to dryness under reduced pressure. The residues are each dissolved in 100 ml. of chloroform. The cboloroform solutions are washed with (a) 50ml. of 0.25% acetic acid, (b) 50 ml. of water saturated with sodium chloride and dried over magnesium sulfate. The dried chloroform solutions of a, c, d, and e are evaporated on the steam bath to 5 ml. and the crystallization is allowed to take place over the weekend. .Aliquot (b) is evaporated to dryness and passed through a'partition column using the procedure described in Example 1. The products are recovered by filtration and washed with chloroform. The following results are obtained:

B rt'tion column A 1 pa 1 O D E Outs 13-16 Cuts 17-20 Cuts 21-24 Wei ht of roduct (gi p 1. 47 1. 0 1 1. 045 0. 061 2. 673 2. 05 2. 559. Wei ht 'eld erce t) Y1 (p 29. 20. 20.9 1.1 53. 41. 61. 5. Polarograohic as- Sa efcent 100. 9L 92.8 93.7 90. 65:5. In lr -r zl spect rum GoodA Good A 011013 Good A CHCla Good A in--- Good Al-l- CHCls Good A Impure A 'solva'te. I solvate. solvate.

A E ZL' 14,445 13,1nn 13,800 14,000- 13, r 14,367 9,954. gptical rotatiolriluu +29.2 +19." @1 19] +172 +20." +20.8 5 21.2.

7 ue tetrazo um I assay (percent) 109.2 .4 89.9 102.5--. 103.7 109. 92-6. Chromatogramfl Homogeneous Homogeneous/3 Homogeneous ALL- HoAm geneous HomogeneousAI-tligmpgeneous .nnnpgfiqs MEGItiDgDOiJltWCJ. 160-211 152-189+ 150185+ ..1 180226 14-5-199+ 157-218 132-185+. Selenium content (p.p.m.) 2504M 40 an 250-400 300.--.-. 90 20.

Without the additional nickel treatment, a gum formed in attempting to isolate a second crop. When the mother liquor of A (this aliquot was originally treated once W-ithone teaspoon of partially deactivated nickeD'was treated with an additional teaspoon of partially deactivated Raney nickel,

additional product was obtained.

NorE.Weight of 2nd crop (g.), 1.28; percent Weight yield, 25.6; polarographic assaylpercent), 77.5; infra-red spectrum, good A A+ CH 01;; a E53,

8-3 mlof the stationary phase with 170-grams of .diatomaceous earth and pack in a 4.5'cmudiameter-column.

Example 2 Asolution ofj25.0 grams of 160:,21-di1C6t0XY-115,170:-

dihydroxy oz-iluoro-4-pregnene-ELZQ-clione in 2100 ml.

oftertiary butyl alcohol is swept with nitrogen. To this solution, 27.5 grams of selenium dioxide dissolvedin 25 urated with sodium'chloride, (b) 100 ml. of water saturated with sodium bicarbonate, (c) three times with 100 portions ofwater saturated with sodium chloride. The washed chloroform solution is dried over magnesium sulfate ,and evaporated under reduced pressure. The

aliquots of ml. of methanol each are prepared and treated with partially deactivated Raney' nickel catalyst as-follows:

(a, b), Each slurried'with 5 ml. of partially deactivated Raney nickel'for two hours. i l

The selenium residue --is Five equal 0 pt ta on, +162; chromatogram A +spot at origin; Blue tetrazoliumassay (percent),.94,4,

Example 3 Twentygrams of 16 21-diacetoxyr11,3,1-7a-dihydroxY 9a-fluoro-4-pregnene-3,ZO-dione is oxidized according to the procedure described inExampleZ for a period of163 hours, An aliquot of the methyl alcohol; solution equivalent to 10 grams of starting 16a,21 diacctoxyvlllfldh-di- -hydroxy-9a-fiuoro-4-pregnene-3,ZO-dione is treated with Raney nickel. catalyst as described in c of Example 2.

Following the nickel treatment, the catalyst is removed by filtration and the filtrate is evaporated to dryness under 7 reduced pressure. The residue is dissolved 700 ml. of chloroform and washed with (a) 50ml. of water saturated with sodium bicarbonate, (b) ml. of water saturated with sodium chloride, (c) 100 ml. of 1% acetic acid, and (d) 50 ml. of water saturated with sodium chloride. The washed chloroform solution is dried over magnesium sulfate and divided into aliquots A and B; each equivalent to 5.0 grams of the starting 16a,21-dia'cetoxy-1 1 1,170:- dihydroxy-9atuoro-4-pregnene-3,QO-dione. Aliquot A is evaporated to dryness under reduced pressure and re- .acetylated in pyridine' with acetic anhydride. The :,21-

:3,20-dione is isolated from chloroform as'described'in Example 2. Aliquot B'is evaporated on the steam bath to 7 ml.; the crystallization is allowed'totake place over a period of 48 hours andthe product is removed by filtra- 'tion. The crystals are washed with chloroform and dried .75 under reduced pressure at SO. ,C. for =l6 hours.

Weight oi product (g.)

Weight yield (percent)- Polarographic assay (percent).

InIra-red spectrum Geod N H-011013.-- Good A "+CHCl3. Xma=.Ef 12, 13,6 Optical rotation Blue tetrazolium assay (percent). Chromatogram Meltint point C C.) 145-19 Selenium content (p.p.m.) 100 Homogeneous A L- A M-spot at origin. 145-195.

Example 4 A further experiment is carried out using 25.0 g. of 16a,21 diacetoxy 1l/S,17a-dihydroxy-9a-fluoro-4pregnone-3,20-dione which is oxidized according to the procedure described in Example 2 for a period of 64 hours. An aliquot of the methyl alcohol solution equivalent to grams of starting l6a,21-diacetoxy-l1,8,l7a-dihydroxy-9afiuoro-4-pregnene-3,20-dione is treated with partially deactivated Raney nickel catalyst and processed to final crystals as described in c of Example 2.

Wt. of product (g.) 8.0

Wt. yield (percent) 53.7.

Polarographic assay (percent) 85.

Blue tetrazolium assay (percent) 93.2.

Infra-red spectrum Weak aliphatic CH; (+CHCh). mi. (Ef

Optical rotation +19.1.

Chromatogram. A plus spot at origin.

Melting point 149.0180 C.+. Selenium content 240.

A second crop was obtained upon further reducing the mother liquor volume and allowing to stand at room temperature.

Wt. of 2nd crop 0g.) 1.91.

Wt. yield (percent) 12.7.

Poiarographic assay (percent) 73.4.

Blue tetrazolium assay (percent) 98.8.

Infra-red spectrum A A maximum is weak (+OHO13). Man. (are)... 00-

Optical rotati +16.7. Ohromatogram- A +iaint spot at origin. Melting point 140-180 (1+.

Selenium content (p.p.m.) 320.

Total weight of l6a,21-diacetoxy-llB,17a-dihydroxy-9afluoro-l,4-pregnadiene-3,20-dione is 9.98 g. representing a yield of 66.4%

Example 5 1st crop 2nd crop Weight of product (g.)

Weight yield percent Polarographic assay (percent) 93.5 99 7 Infra-red spectrum Good A Am, ET1;, 13,680. 13,800. Optical ro +85 0 +885 0. Chromatogram A and A A and A Melting point C.) 227.2-238 2333-23715. Selenium content (p. 00 250-400.

Example 6 To five grams of 160:,2l-diacetoxy-lh-hydroxy-4- pregnene-3,l l,20-trione dissolved in 500 ml. tertiary butanol is added five grams of selenium dioxide in five cc. of water. The flask is swept with nitrogen and refluxed at 8082 C. for 68 hours. The selenium isfiltered off. The filtrate is evaporated to dryness and the residue dissolved in 200 ml. chloroform. Inorganic selenium salts are filtered off. Two ml. portions of saline solution are used to wash the chloroform solution which is then dried over magnesium sulfate and evaporated to dryness. Weight of crude is 6.25 grams. The crude product is dissolved in ml. methanol, heated to 60 C., and about seven grams of partially deactivated Raney nickel (slurried in ethanol) is added. After slurrying at 60 C. for 20 minutes, the filtrate is evaporated to dryness. The residue is dissolved in 100 ml. of chloroform. Two 50 ml. portions of saline solution are used to wash the chloroform solution, and the chloroform extract is dried over magnesium sulfate. The solution is filtered and evaporated to dryness. The weight of the crude pr not is 5.06 grams. The crude product is dissolved in 25 ml. of toluene, 200 ml. of ether added and filtered. The filtrate is evaporated to dryness, and the resulting residue is dissolved in 15 m1. toluene. The solution is heated and 4 ml. of petroleum ether added to crystallize out the final product. The 16:1,2l-diacetoxy-l7a-hydroxy-1,4- pregnadiene-Za,1l,20-trione weighs 1.15 grams.

1st crop 2nd crop Weight of prorlnr-t 1.15 g 2.9 g. Weight yield (percent) 23 58.0 g. Infra-red spectrum Good A Am. E12; 14,080-- Optical rotation +89.4 Ohromatogram 1 .4 r .4 Melting point C 0.) 205-208 202-206.

Analysis.Calcd C H O Found Oalcd C 65.71 65. 4 "FT 7. 09 6. 59 0 acetyl 18. 25 18. 74

We claim:

1. In a process for the preparation of 3-keto-1,4-pregnadienes having the general formula:

CHzOR in which R is a member of the group consisting of hydrogen and lower alkanoyl radicals, R is a member of the group consisting of hydrogen, hydroxyl and lower alkanoyloxy radicals and -X-X is a trivalent ethylene radical of the group consisting of l l HO-C-C-Hal alkanoyloxy-l1/3,17a-dihydroxy 9u-halo 1,4 pregnadiene-3,20-dione which comprises reacting 16u,21-dilower alkanoyloxy 116,170: dihydroxy-9a-halo 4-pregnene- 3,20-dione with selenium: dioxide, removing residual selenium, subjecting the reaction product to partially deactiyated Raney nickel catalyst at a temperature within the range of 0 to 50 C. and recovering said compounds therefrom substantiallyfree from other steroids.

5. In a method of preparing 16a,21-diloweralkanoy1- oxy-l1p,17a-dihydroxy-9a-halo 1,4 pregnadiene-330- diones of increased purity from 16a,21-dilower alkanoyloxy-l113,17a-dihydroxy-9a-halo-4 pregnene 3,20 diones by selenium oxidation, the step which comprises subjecting the selenium oxidation reaction product to partially deactivated'Raney nickel catalystat a temperature within the range of (Ho 50 C. and recoveringsaid product therefrom substantially freefrom other steroids.

6. An improved method of preparing 2l-acetyloxy- 113,170; dihydroxy19afluoro-l,4-pregnadiene-3,20-dione which comprises reacting 21-acetyloxy-115,17a-dihyd aryo -pregnene-3,ZO-dione with selenium .dtv oxide, removing residual selenium, subjecting the reaction product to partially deactivated Raney nickel catalyst at a temperature Within the range of 0 to 50 C. and recovering said compound therefrom substantially :free from other steroids.

7. An improved method of preparing 16oz,21-dilower alkanoyloxy-l1,8,17wdihydroxy-9a-halo 1,4 --pregnadiene-3,20-dione which comprises reacting 16,21-dilower alkanoyloxy-l15,17a-dihydroxy 9a halo:4-pregnene- 3;20-dione with selenium dioxide, removing residual selenium, subjecting the reaction product to partially deactivated Raney nickel previously treated with acetic acid at a temperature within the range of 0 to 50 C. and recovering said compounds therefrom substantially free from other steroids.

References'Cited in the file of this patent UNITED STATES PATENTS OTHER REFERENCES Szpilfogel: Recueil des Travaux Chimiques des Pays- Bas, May 1956, pages 475-480. 

1. IN A PROCESS FOR THE PREPARATION OF 3-KETO-1,4-PREG NADIENES HAVING THE GENERAL FORMULA: 